SIGNIFICANCE: Melanoma incidence is rising faster than any other cancer and metastatic melanoma is typically fatal. Responses to targeted and immunotherapies can be remarkable, but low response rates, acquired resistance, and adverse side effects limit long-term quality of life for these patients. The overall response rate to all therapies remains dismally near 50% and the 5-year survival is <25%. Preclinical studies have identified radiolabeled peptides that target the melanocortin receptor 1 (MC1R) as a potential therapeutic alternative. While this approach using ?-particle emitters has been largely ineffective preclinically, previous publications and our Phase I data have demonstrated efficacy of Viewpoint?s MC1R-targeted VMT01 ?-particle therapy in mice bearing melanoma tumors. Thus, VMT01 is designed to meet the significant unmet medical need to improve outcomes for these patients (initial indication of progressive stage 4 metastatic melanoma), with potential for expanded indications in combination with FDA-approved melanoma drugs (e.g., immunotherapies). In this revised Phase II SBIR project, Viewpoint will complete a Phase 1 first-in-human clinical trial to determine the safety of its companion diagnostics. It is further expected that the company will have gained a preliminary understanding of the effectiveness of [68Ga]VMT02 imaging (PET) to identify MC1R positive tumors and the utility of [203Pb]VMT01 imaging (SPECT) for performing patient dosimetry for personalized [212Pb]VMT01 ?-therapy. PREDICATE PHASE I MILESTONES include: efficacy (therapy and imaging) in mice; pharm/tox of lead VMT01; automated radiopharmaceutical production with GMP kits; exclusive licenses to IP; clinical consortium with Mayo Clinic and 203Pb supply with Lantheus Medical Imaging; CRO for statistics/clinical data (Compleware, Inc.); and a radiopharmacy partner (Hotshots Nuclear Medicine) for manufacturing/distribution of [203Pb]VMT01. EQUITY INVESTMENTS: Viewpoint has secured $650,000 in equity investment to establish manufacturing of 212Pb generators for future clinical therapy trials. The company will complete the following Aims toward its goals. AIM 1. Secure FDA ?safe to proceed? designation to conduct the Phase 1 imaging trial of [203Pb]VMT01 and [68Ga]VMT02 under IND. AIM 2. Complete a Phase 1 safety and biodistribution study of [203Pb]VMT01 and [68Ga]VMT02 imaging in human subjects and demonstrate their utility for identifying MC1R positive tumors and performing patient-specific dosimetry. OUTCOMES: We expect to demonstrate the clinical safety of [203Pb]VMT01 and [68Ga]VMT02. We further expect to develop preliminary understanding of the efficacy of [68Ga]VMT02 PET/CT to identify MC1R+ tumors and the utility of [203Pb]VMT01 SPECT/CT for patient-specific dosimetry for [212Pb]VMT01 ?-therapy. Thus, we will be prepared to initiate dosimetry-based trials of [212Pb]VMT01 ?-particle therapy for metastatic melanoma to be funded under Phase IIB SBIR studies and Phase III equity investments.